Fatigue in rheumatoid arthritis patients: The status, independent risk factors, and consistency of multiple scales

Abstract Introduction Fatigue is a common symptom that negatively affects the outcomes and functions of rheumatoid arthritis (RA) patients. This study aimed to assess the fatigue by two scales and validate their consistency, also to comprehensively evaluate fatigue‐related risk factors in RA patients. Methods In this case–control study, the fatigue of 160 RA patients and 60 healthy controls was evaluated by the Bristol Rheumatoid Arthritis Fatigue Multi‐Dimensional Questionnaire (BRAF‐MDQ) and the Chinese version of the Brief Fatigue Inventory (BFI‐C). The 28‐joint disease activity score using erythrocyte sedimentation rate of RA patients was assessed. Results The BRAF‐MDQ and BFI‐C scores were elevated in RA patients versus healthy controls (all p < .001). Interestingly, BRAF‐MDQ global fatigue score positively correlated with BFI‐C global fatigue score in both RA patients (r = .669, p < .001) and healthy controls (r = .527, p < .001); meanwhile, Kendall's tau‐b test showed a high consistency between BRAF‐MDQ and BFI‐C global fatigue scores in RA patients (W = 0.759, p < .001) and healthy controls (W = 0.933, p < .001). Notably, higher education level (В = −4.547; 95% confidence interval: −7.065, −2.029; p < .001) and swollen joint count (В = 1.965; 95% confidence interval: 1.375, 2.554; p < .001) independently related to BRAF‐MDQ global fatigue score; higher education level (В = −0.613; 95% confidence interval: −0.956, −0.269; p = .001) and clinical disease activity index (В = 0.053; 95% confidence interval: 0.005, 0.102; p = .032) independently linked with BFI‐C global fatigue score. Conclusion Fatigue commonly occurs in RA patients, which independently relates to education level and disease activity. Furthermore, BRAF‐MDQ and BFI‐C scales exhibit a high consistency in assessing fatigue.

2][3] Although fatigue in RA can be partially explained by inflammation, it may be more likely to be due to factors that are indirect to the disease, such as behavioral and psychological factors. 4][7][8] Therefore, exploring the fatigue condition and related risk factors may contribute to the management of fatigue and improve the prognosis of RA patients.
0][11][12][13][14] For example, one recent study shows that fatigue occurrence is 62%; meanwhile, education level and disease activity are related to fatigue score in RA patients. 9Simultaneously, another study indicates that some factors are associated with fatigue in RA patients, such as age, disease duration, functional disability, quality of life, and so on. 10Additionally, one previous study reveals that mental health and pain are important predictors of fatigue in RA patients. 11One study illustrates that RA patients experience greater fatigue during the winter. 12Moreover, some previous studies also exhibit that sleep disorders and comorbidities (such as hypertension, hypothyroidism, and deficiency anemias) are linked with fatigue in RA patients. 13,14However, the gap of the above studies is that the vast majority of these studies use a single scale for fatigue evaluation in RA patients.More importantly, few studies verify the consistency among different scales for fatigue evaluation in RA patients.
The Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) is a fatigue assessment scale designed in collaboration with RA patients. 15Different from other scales, BRAF-MDQ uniquely measures fatigue from four separate dimensions, which fully captures fatigue from the patient's perspective. 16Currently, BRAF-MDQ has been widely used in clinical studies internationally. 17In addition, the Brief Fatigue Inventory (BFI) is also a fatigue assessment scale for RA patients, which is characterized by brevity and ease of understanding. 18The original BFI is translated into multiple languages, among which the Chinese version of the BFI (BFI-C) provides a valid and reliable fatigue assessment instrument for Chinese RA patients. 18Considering the above advantages of BRAF-MDQ and BFI-C, we choose these two scales for fatigue assessments in RA patients.Meanwhile, to apply simple scales to replace complex scales for fatigue evaluation in clinical practice, our study also assessed the consistency between BRAF-MDQ and BFI-C scales.
Therefore, our study applied BRAF-MDQ and BFI-C scales to comprehensively evaluate fatigue and validate the consistency between scales; meanwhile, this study also aimed to assess the risk factors of fatigue in RA patients.

| Subjects
From December 2022 to February 2023, 160 RA patients treated in the Affiliated Suqian First People's Hospital of Nanjing Medical University were consecutively enrolled in this case-control study.The enrollment criteria contained the following: (i) diagnosis of RA per 1987 American College of Rheumatology (ACR) criteria or 2010 ACR/European League Against Rheumatism criteria 19,20 ; (ii) aged ≥ 18 years old; (iii) were voluntary for participation and signed the informed consent.The exclusion criteria contained the following: (i) had a prior history of malignancies, psychiatric diseases, neurological diseases, or major surgeries; (ii) had moderate-tosevere cognitive impairment to complete the questionnaire.Besides, 60 healthy subjects were enrolled as healthy controls with the following screening criteria: (i) had normal physical and biochemical indicators on physical examinations; (ii) aged ≥ 18 years old; (iii) had capable of accomplishing questionnaires; (iv) had no history of tumors, psychiatric diseases, neurological diseases, and major surgeries; and (v) volunteered to participate in the study and signed informed consent form.The Ethics Committee of the Affiliated Suqian First People's Hospital of Nanjing Medical University approved this study (approval number: 20230005).

| Data collection
Clinical characteristics of RA patients were obtained after enrollment, which included (i) demographics: age, gender, body mass index (BMI), education level, marital status, employment status, and location (determined based on the information of patients' identity cards); (ii) disease history: hypertension, hyperlipidemia, and diabetes; (iii) disease characteristics: disease duration, rheumatoid factor-positive, anticitrullinated protein autoantibody-positive, tender joint count (TJC), swollen joint count (SJC), erythrocyte sedimentation rate (ESR), C-reactive protein, 28-joint disease activity score using ESR (DAS28 ESR score), patient's global assessment score, physician's global assessment score, and clinical disease activity index (CDAI) score 21,22 ; (iv) treatment.Exposure variables included the clinical characteristics of RA patients (demographics, disease history, disease characteristics, and treatment).

| Evaluation
Fatigue of RA patients and healthy controls were evaluated based on BRAF-MDQ and BFI-C after enrollment. 18,23BRAF-MDQ contains 20 items and encompasses a global score (Score 0-70) as well as physical (Score 0-22), living (Score 0-21), cognitive (Score 0-15), and emotional (Score 0-12) subdomain scores.The higher score indicates a more severe fatigue level.BFI-C contains nine items and encompasses fatigue severity (mean value of three items) and fatigue interference (mean value of six items), and a global score is the mean value of nine items (Score 0-10).The higher score reflects the greater fatigue level.Functional disability and quality of life in RA patients were evaluated using Health Assessment Questionnaire Disability Index (HAQ) and short-form health survey (SF12) scores, respectively.

| Statistics
SPSS v22.0 (IBM Corp.) was adopted for analysis.GraphPad Prism v7.0 (GraphPad Software Inc.) was adopted for graph plotting.T test was utilized for groupcomparison analysis.Pearson's correlation test and Spearman correlation test were utilized for correlation analysis.Kendall's tau-b test were utilized for consistency evaluation, and the consistency coefficient (W) > 0.7 was considered a good degree of consistency. 24Linear regression analysis was utilized for screening the factors related to fatigue.p < .05 was considered significant.

| Baseline features of RA patients and healthy controls
The enrolled RA patients had a mean age of 57.9 ± 11.5 years with 44 (27.5%) males and 116 (72.5%) females.Meanwhile, healthy controls had a mean age of 48.5 ± 13.4 years with 22 (36.7%)males and 38 (63.3%) females.Notably, the mean age of RA patients was older than healthy controls (p < .001);meanwhile, there was a difference in education level between RA patients and healthy controls (p = .005).Moreover, there was no difference in gender (p = .186)or BMI (p = .146)between RA patients and healthy controls.More detailed characteristics were listed in Table 1.
In addition, the functional disability assessed by HAQ and quality of life evaluated by SF12 in RA patients were shown in Supporting Information S1: Table 1.

| Comparison of BRAF-MDQ and BFI-C score between RA patients and healthy controls
Regarding the BRAF-MDQ score, the global fatigue score was elevated in RA patients compared with healthy controls (p < .001).Simultaneously, the physical fatigue score (p < .001),living fatigue score (p < .001),cognition fatigue score (p < .001),and emotion fatigue score (p < .001)were all increased in RA patients compared with healthy controls (Figure 1A).
In terms of the BFI-C score, the global fatigue score was also increased in RA patients compared with healthy controls (p < .001).In addition, the fatigue severity score (p < .001)and fatigue interference score (p < .001)were both elevated in RA patients compared with healthy controls (Figure 1B).

| Factors correlated with BRAF-MDQ-evaluated global fatigue score in RA patients
Univariate linear regression analysis exhibited that higher education level was related to lower global fatigue score evaluated by BRAF-MDQ, while TJC, SJC, ESR, DAS28 ESR score, and CDAI score were correlated with higher global fatigue score evaluated by BRAF-MDQ in RA patients.Further multivariate linear regression analysis revealed that higher education level was independently related to lower global fatigue score evaluated by BRAF-MDQ (В = −4.547,p < .001),but SJC was independently related to higher global fatigue score evaluated by BRAF-MDQ in RA patients (В = 1.965, p < .001)(Table 2).

| Factors correlated with BFI-Cevaluated global fatigue score in RA patients
Univariate linear regression analysis observed that higher education level and biologic disease-modifying antirheumatic drugs treatment were associated with lower global fatigue score evaluated by BFI-C, but the rural location, TJC, SJC, ESR, DAS28 ESR score, and CDAI score were linked with higher global fatigue score evaluated by BFI-C in RA patients.Next, multivariate linear regression analysis showed that higher education level was independently correlated with lower global fatigue score evaluated by BFI-C (В = −0.613,p = .001);however, CDAI score was independently related to higher global fatigue score evaluated by BFI-C in RA patients (В = 0.053, p = .032)(Table 3).

| Association of methotrexate administration with fatigue reflected by BRAF-MDQ and BFI-C in RA patients
There was no discrepancy in fatigue scores assessed by BRAF-MDQ between RA patients treated with methotrexate administration and those without (all p > .05).In terms of fatigue scores assessed by BFI-C, no difference was observed between RA patients treated with methotrexate administration and those without (all p > .05)(Table 4).

| Association of educational level with SJC and CDAI score in RA patients
The education level was negatively linked with SJC (r = −0.339,p < .001),but not correlated with CDAI score (r = −0.056,p = .480)in RA patients (Table 5).Additionally, in RA patients with SJC high (>3.0), the educational level was not linked with BRAF-MDQ or BFI-C scores (all p > .05).However, in RA patients with CDAI score high (>18.0), the educational level was inversely associated with BRAF-MDQ and BFI-C scores (all p < .05)(Table 6).

| Association of educational level with fatigue in healthy controls
Regarding the BRAF-MDQ score, the educational level was inversely correlated with physical fatigue score (p = .001);however, it was not correlated with global fatigue, living fatigue, cognition fatigue, or emotion fatigue scores in healthy controls (all p > .05).Moreover, the educational level was not correlated with BFI-C scores in healthy controls (all p > .05)(Supporting Information S1: Table 2).Univariate linear regression analysis showed that higher education level was not related to BRAF-MDQ or BFI-C scores in healthy controls (both p > .05)(Supporting Information S1: Table 3).

| Correlation and consistency between BRAF-MDQ and BFI-C
Notably, the global fatigue score evaluated by BRAF-MDQ was positively associated with the global fatigue score assessed by BFI-C in RA patients (r = .669,p < .001)(Figure 2A) and healthy controls (r = .527,p < .001)(Figure 2B).Furthermore, Kendall's tau-b test indicated that there was a high consistency between BRAF-MDQ and BFI-C in RA patients (W = 0.759, p < .001)and healthy controls (W = 0.933, p < .001).

| DISCUSSION
6][27] As a common chronic symptom in RA patients, fatigue brings great burdens to patients, including daily activity obstacles, decreased work ability, economic loss, and so on. 28,291][32] Similar to these studies, our study presented that the fatigue scores reflected by BRAF-MDQ and BFI-C scale were increased in RA patients compared with healthy controls.The possible reasons for fatigue in RA patients were as follows: (1) RA patients had high levels of inflammation, which was considered to be positively correlated with fatigue. 25,33(2) RA patients had reduced self-efficacy, low mood, poor sleep at night, and so on, which might also induce fatigue. 26Therefore, the fatigue score was higher in RA patients.
Exploring the risk factors of fatigue for early management is of great significance for the treatment of RA patients.One previous study shows that female sex, functional capacity, physical pain, mental health, and disease activity are risk factors for fatigue in RA patients. 32Furthermore, one study finds that pain, morning stiffness, hemoglobin, joint tenderness, and disease activity are associated with fatigue in RA patients. 6Another study exhibits that age, education, hypertension, disease activity, and other factors are correlated with fatigue in RA patients. 9Our study found that education level and disease activity were independent risk factors of fatigue reflected by the BRAF-MDQ and BFI-C scales.The possible explanations were as follows: (1) RA patients with a high education level might have a better understanding of the disease and good medication adherence 34 ; meanwhile, they received more social support when facing disease symptoms, which was considered to be imperative in coping with fatigue. 35,36The above advantages might alleviate fatigue symptoms.Furthermore, RA patients with a low education level might be more inclined to work in manual jobs, which increased their fatigue. 37(2) Disease activity reflected the disease status.RA patients with high disease activity might have additional joint pain and elevated inflammation, which caused severe fatigue. 6,31,38(3) Our study used BRAF-MDQ and BFI-C scales to assess fatigue, which was different from scales used in other previous studies. 6,9,32Moreover, differences in the included population between our study and other previous studies might cause different results.Therefore, there might be some differences in factors related to fatigue between our study and other previous studies.Notably, there was a difference in age between RA patients and healthy controls in our study, thus our study further assessed whether age was related to fatigue in RA patients.The result suggested that age was not independently related to global fatigue score evaluated by BRAF-MDQ or by BFI-C in RA patients.The finding of our study indicated that fatigue in RA patients might be caused by the disease itself rather than age.Moreover, there was a difference in education level between RA patients and healthy controls in our study.To further explore whether the correlation between education level and fatigue is universal or RA-specific, our study investigated the correlation of education level with fatigue in healthy controls and found a very weak correlation.Meanwhile, higher education level was not an independent risk factor of fatigue reflected by the BRAF-MDQ and BFI-C scales in healthy controls.This finding indicated that the correlation between education level and fatigue was RA-specific.Interestingly, our study found that risk factors associated with fatigue in RA patients were slightly different between the BRAF-MDQ scale and the BFI-C scale.The risk factors for fatigue in RA patients assessed by the BRAF-MDQ scale were higher education level and SJC, while the risk factors for fatigue in RA patients evaluated by the BFI-C scale were high education and SJC.The difference between the two scales might be due to their different modes of questioning RA patients: The BRAF-MDQ scale consulted RA patients in detail whether their living conditions were affected by fatigue. 7However, the BFI-C scale directly asked RA patients to score for fatigue. 18Thus, it was hypothesized that different modes of questioning patients from the two scales might have a certain influence on the risk factor assessment of fatigue in RA patients.Nevertheless, further verification was required for this hypothesis.
The current drugs for RA mainly include nonsteroidal anti-inflammatory drugs, glucocorticoids, and DMARDs. 39Notably, some studies exhibit that the use of DMARDs alleviates fatigue compared to placebo in RA patients. 40,41However, there is no difference in the effect of different drugs on fatigue in RA patients. 25,42For example, one previous study shows that the type of medicine is not related to fatigue in RA patients. 42nother study also illustrates that different drug treatments did not affect fatigue severity in RA patients. 25The result of our study was similar to the findings of these above studies, 25,42 which revealed that specific drug regimens were not independently linked with fatigue in RA patients.
In addition, due to the different evaluation emphasis of each scale, there may be some discrepancies in fatigue assessment when using diverse scales in RA patients. 430][11] Therefore, our study included the BRAF-MDQ scale and BFI-C scale, then confirmed their good consistency in assessing fatigue scores in RA patients.Considering that it is more convenient to use the BFI-C scale than the BRAF-MDQ scale, 18,44 the BFI-C scale could be considered as a substitute of the BRAF-MDQ scale to evaluate the fatigue score in RA in clinical practice.
Notably, there are many different scales to evaluate fatigue, while few studies use multiple scales for fatigue evaluation and verify their consistency.Our study evaluated fatigue by two scales (the BRAF-MDQ and the BFI-C scales), and then validated their consistency in RA patients.The result of our study showed that the BRAF-MDQ and the BFI-C scales exhibited a high consistency in the clinical assessment of fatigue in RA patients, which was not reported in previous studies.Based on the results of our study, future studies should consider expanding the sample size or longitudinally assessing the fatigue of RA patients for further verification.
There were several limitations in this study: (1)  The number mismatch between RA patients and healthy controls might interfere with the statistical effect.(2) Although the sample size in our study was relatively large (N = 160), further studies should consider including an even greater sample size to obtain a clearer conclusion.(3) Our study was crosssectional, and longitudinal studies with repeat measures are needed to further explore risk factors of fatigue.(4) Our study was performed in a single center in China, and the results might not be applicable to the general population.
In conclusion, fatigue is prevalent and its risk factors include low education level and high disease activity in RA patients.Fatigue in RA patients is not influenced by different medical treatments for RA.Moreover, fatigue assessment by BFI-C and BRAF-MDQ scales are interchangeable.

( 1 )
According to the BRAF-MDQ score, the global fatigue score, the physical fatigue score, living fatigue score, cognition fatigue score, and emotion fatigue score were increased in RA patients compared with healthy controls.(2) Based on the BFI-C score, the global fatigue score, the fatigue severity score, and fatigue interference score were elevated in RA patients compared with healthy controls.(3) Higher education level and SJC independently related to BRAF-MDQ global fatigue score; higher education level and CDAI independently linked with BFI-C global fatigue score in RA patients.(4) There was a high consistency between BRAF-MDQ and BFI-C global fatigue scores in RA patients and healthy controls.

F
I G U R E 1 BRAF-MDQ and BFI-C score in RA patients and healthy controls.Comparison of BRAF-MDQ score (A) and BFI-C score (B) between RA patients and healthy controls.BRAF-MDQ, Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire; BFI-C, the Chinese version of the Brief Fatigue Inventory; RA, rheumatoid arthritis.

F I G U R E 2
Correlation of BRAF-MDQ with BFI-C score in RA patients and healthy controls.The relationship between BRAF-MDQ score and BFI-C score in RA patients (A) and healthy controls (B).BFI-C, the Chinese version of the Brief Fatigue Inventory; BRAF-MDQ, Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire; RA, rheumatoid arthritis.
Clinical characteristics.
T A B L E 1 Linear regression analysis for global fatigue of BRAF-MDQ.Variables in the univariate linear regression analysis were included in the multivariate linear regression analysis with the forward stepwise method.
T A B L E 4 Correlation of methotrexate administration with fatigue in RA patients.Correlation of educational level with SJC and CDAI score in RA patients.Correlation of educational level with fatigue in RA patients with high SJC or CDAI score.
T A B L E 6